The hypocretins, also known as orexins, are excitatory neuropeptides produced in the lateral hypothalamus, which have a key role in the regulation of arousal. Hypocretin deficiency in dogs, mice and humans causes narcolepsy, a sleep disorder characterized by excessive daytime sleepiness and cataplexy. Hypocretin-containing neurons project to key structures involved in brain reward, most notably the nucleus accumbens, central amygdala and bed nucleus of stria terminalis. Since stress may represent an overactivation of the body's normal activational system and therefore is linked to the construct of arousal, we hypothesize that hypocretins may mediate at least in part, the activation of stress-induced signals that precipitate addiction and relapse. Under this proposal we will test three hypotheses: 1) that hypocretin neurons activate a "stress-like" response that results in reinstatement of cocaine seeking behavior;2) that hypocretin signaling is important for stress and cue-induced reinstatement of cocaine seeking behavior, and 3) that hypocretin deficient mice are resistant to drug abuse. In a first specific aim, mice with a history of cocaine self-administration and extinction will be infused with hypocretin and tested for reinstatement of cocaine seeking behavior. To determine whether stress signals are involved in hypocretin-induced reinstatement, mice deficient in corticotrophin release factor (CRF) receptor 1 will be tested for reinstatement of cocaine seeking behavior after hypocretinl infusion. Hypocretin-induced reinstatement will be blocked with hypocretin receptor antagonists and (CRF) receptor antagonists. In a second specific aim, the role of endogenous hypocretin on reinstatement will be tested by using a hypocretin receptor antagonist to block stress or cue- induced reinstatement. Accumulated clinical data has shown that hypocretin-deficient narcoleptic patients rarely abuse psychostimulants that are used to treat excessive daytime sleepiness. In specific aim 3, we will further examine whether hypocretin-deficient animals are resistant to stimulant abuse by amphetamine conditioned place preference test and by amphetamine and cocaine self administration. Finally, hypocretin-deficient mice will be tested for stress- and cue- induced reinstatement of cocaine or amphetamine seeking behavior. The results from these experiments will give us important clues about the role of the hypocretinergic system in brain reward and may result in new therapeutic tools to prevent drug craving and relapse.